This application for renewal proposes to continue our investigation of novel mechanisms involved in insulin regulation of hepatic glucose fluxes. Our long-term goal has been to improve our understanding of the link between nutrient availability and liver glucose output. During the last funding period we demonstrated that bi-directional changes in hypothalamic insulin signaling can regulate liver glucose homeostasis in mice and rats. Here we wish to investigate the biochemical signaling steps required for these effects and how they are modified in insulin resistant models. Specifically, we wish to examine the following questions: 1. Does insulin regulate hepatic glucose fluxes via activation of PI(3)K/Akt-dependent pathways within the mediobasal hypothalamus? 2. Does insulin regulate hepatic glucose fluxes via activation of FOXO1- and/or nNOS- dependent pathways within the mediobasal hypothalamus? 3. Does insulin inhibit hepatic glucose production when the activation of hypothalamic malonyl-CoA-dependent pathways is prevented? 4. Is the activation of hypothalamic insulin signaling sufficient to rescue hepatic insulin action in genetic mouse models of hypothalamic insulin resistance? 5. Is the activation of hypothalamic insulin signaling sufficient to rescue hepatic insulin action in a rat model of diet-induced hepatic insulin resistance? The experiments proposed in this application should allow us to clarify the early biochemical events necessary for hypothalamic insulin signaling and how they are modified in animal models of hepatic insulin resistance.